肿瘤细胞治疗研究
英文原题：IL-21/IL-21R signaling renders acute myeloid leukemia stem cells more susceptible to cytarabine treatment and CAR T cell therapy.
IL-21/IL-21R signaling renders acute myeloid leukemia stem cells more susceptible to cytarabine treatment and CAR T cell therapy.
白血病干细胞（LSCs）的自我更新程序预示急性髓系白血病（AML）患者预后不良。
白血病干细胞（LSC）的自我更新程序可预测急性髓系白血病（AML）患者预后不良。我们发现，CD4+ T细胞来源的白细胞介素（IL）-21是LSC自我更新的重要负调节因子。IL-21/IL-21R信号通过激活p38-MAPK通路，促进LSC不对称细胞分裂和分化，从而减少LSC数量，并显著延长小鼠AML模型的生存期。在人AML中，确诊时血清IL-21被确定为结局的独立有利预后生物标志物；在接受大剂量化疗的患者中，血清IL-21与生存改善和完全缓解率较高相关。IL-21处理可抑制原代LSC功能，并在体外增强阿糖胞苷及CD70 CAR T细胞治疗对LSC的作用。在同系移植和异种移植实验中，低剂量IL-21治疗均延长了AML小鼠生存期。因此，促进LSC中的IL-21/IL-21R信号可能有助于降低AML干性并促进分化。
Self-renewal programs in leukemia stem cells (LSCs) predict poor prognosis in patients with acute myeloid leukemia (AML). We identify CD4 + T cell-derived interleukin (IL)-21 as an important negative regulator of self-renewal of LSCs. IL-21/IL-21R signaling favors asymmetric cell division and differentiation in LSCs through the activation of p38-MAPK signaling, resulting in reduced LSC numbers and significantly prolonged survival in murine AML models. In human AML, serum IL-21 at diagnosis is identified as an independent positive prognostic biomarker for outcome and correlates with improved survival and higher complete remission rates in patients that underwent high-dose chemotherapy. IL-21 treatment inhibits primary LSC function and enhances the effect of cytarabine and CD70 CAR T cell treatment on LSCs in vitro. Low-dose IL-21 treatment prolongs the survival of AML mice in syngeneic and xenograft experiments. Therefore, promoting IL-21/IL-21R signaling on LSCs may be an approach to reduce stemness and increase differentiation in AML.
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